The aim of this program is to further our understanding of the biology of hematopoietic stem cells and apply this knowledge to develop effective strategies for gene therapy. In studies evaluating novel mechanisms that may provide insights into the regulation of the proliferation and differentiation of stem cells, we will investigate the role of stem cell interactions mediated by the Drosophila developmental gene, Notch, in determining the fate of stem cells (Project I); methods for enhancing the activity of retinoic acid receptors to encourage stem cell maintenance and self renewal (Project II); cell cycle control by the CDK inhibitor, p27, in hematopoietic stem differentiation (Project IV). Results of these efforts will be applied in preclinical and clinical studies of the retroviral- mediated transduction of hematopoietic stem cells. In studies to improve our ability to transduce stem cells, we will investigate the determinants of retrovirus vector entry and integration into the genome of stem cells (Project V), and in non-human primates, we will investigate methods for mobilization of stem cells and novel vectors to achieve optimal susceptibility to retrovirus-mediated gene transfer and whether marrow ablation is required for high-level engraftment (Project VI). We will evaluate advances in enhancing gene transfer into hematopoietic stem cells derived from projects in this SCOR, using the human genetic immunodeficiency disease, leukocyte adherence deficiency (LAD), and the disease specific canine model (Project VII). Central to the success of these trials are Core programs which will provide murine, canine, non-human primate, and human hematopoietic precursor cells and prepare retrovirus for preclinical and clinical studies. By brining together investigators with a range of expertise related to hematopoiesis and those with expertise in more basic cellular mechanisms, the SCOR program provides the necessary mechanism for generating novel approaches in this research arena.